We invented an innovative protein induced Pluripotent Stem Cells (piPSCs) technology that generates piPSCs from normal fibroblast and cancer cells within 1-week with 904% conversion efficiency. Such high conversion efficiency enables us to pioneer an in situ cell reprogramming technology within the cancers of cancer-bearing animals. Instead of generating iPSCs in a dish, we perform cell reprogramming in vivo to convert cancer cells into piPSCs that immediately differentiate into non-cancerous cells inside tissues, allowing cancerous tissues to be repaired by normal cells. Using a subcutaneous cancer rat model, we demonstrated that this protein-induced pluripotency- based in situ cell reprogramming provided an effective cell-converting therapy to cure subcutaneous glioma via the in situ conversion of malignant glioma cells into iPSCs for differentiation into non- cancerous cells under the differentiation tissue environment. We applied our QQ-protein delivery technique and daily intra-tumor injections to deliver Sox2, Oct4 and Nanog (SON) proteins directly into the cancer cells to initiate and execute this novel cancer cell conversion. In this proposal, we will optimize this in situ cell reprogramming technology using the same cancer rat model. Two injection methods will be performed to treat subcutaneous glioma-bearing rats: intra- tumor (Aim 1) and intravenous injections (Aim 2). Our goal is to achieve nearly 100% subcutaneous glioma cured rats to provide proof-of-principle data of high efficacy of diseased tissue repair using this technology. In order to achieve this goal, we will optimize the SON protein dosages, injection frequency and period and different QQ-modifications to treat early and late state subcutaneous implanted gliomas. We will also collect safety data of this treatment by measuring tissue distributions and possible pathological changes in the organs caused by the injected SON proteins. Although subcutaneously implanted glioma rat model is not a physiological animal model for human glioma, this model provides a convenient and effective cancer animal model for us to optimize this innovative technology which is the central focus of this Phase I STTR proposal. The success of this proposal will allow us to develop a paradigm-shifting cell reprogramming technology to treat many diseases using the Nobel-winning iPSC concept. This will also provide QURGEN Inc. with many commercialization possibilities. The success of this proposal will further position us to pursue glioma treatment using physiologically relevant intracranial implanted human glioma nude rat models.